Magnesium bistrifluoromethanesulfonimide as a new and efficient acylation catalyst

Article abstract of DOI:10.1021/jo0605142

Magnesium bistrifluoromethanesulfonimide catalyzed the acetylation of phenols, alcohols, and thiols under solvent-free conditions at room temperature and in short times. Electron-deficient and sterically hindered phenols provided excellent yields. The catalyst was found to be general for acylation with other anhydrides, such as propionic, isobutyric, pivalic, chloroacetic, and benzoic anhydrides. The rate of acylation was influenced by the electronic and steric factors associated with the anhydride. The reaction with less electrophilic anhydrides (e.g., chloroacetic and benzoic anhydrides) required higher temperature (～80 °C). Chemoselective acetylation, pivalation, and benzoylation took place with acid-sensitive alcohols without any competitive dehydration/rearrangement.

Full text of DOI:10.1021/jo0605142

efforts to prepare the catalysts [Bi(OTf)3, Nafion-H, yttria-
zirconia, AlPW12O40, and Mn(haacac)Cl]; (v) the lack of atom
economy (use of excess of acetylating agents); (vi) stringent
reaction conditions and the requirement of longer reaction times;
and (vii) in many cases, the reported acylation methodolo-
gies are applicable to alcohols only and are not suitable for
acid-sensitive substrates. Thus, there is a need for the develop-
ment of a mild and cost-effective catalyst for the acylation
reaction.
Magnesium Bistrifluoromethanesulfonimide as a
New and Efficient Acylation Catalyst
Asit K. Chakraborti* and Shivani
Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER),
Sector 67, S. A. S. Nagar 160 062, Punjab, India
In continuation of our efforts for the development of newer
and efficient methods for acylation,4 we report that Mg(NTf2)2
is a new, efficient, and easily accessible acylation catalyst.
While designing the catalyst, we thought that a metal salt
derived from a strong protic acid should be an ideal contender.
The large negative H0 value of -14.1 for TfOH5 makes TfOH
the strongest protic acid, and thus metal triflates have drawn
the attention as acylation catalysts.3 However, TfOH is often
liberated from metal triflates during the triflate-catalyzed
acylation reactions and may be the actual catalytic agent.6 The
in situ generation of TfOH might be the reason for the potential
side reactions (e.g., dehydration, rearrangement, etc.) with acid-
sensitive substrates. Thus, metal-triflate-catalyzed acylation
reactions are often carried out at low temperatures (-8 to -60
°C) and in the presence of an excess of the acetylating agents.
This has led us4a-c and others2d,f,g to develop acylation catalysts
derived from HClO4 as it is weaker than TfOH. However, the
potential hazard associated with HClO4 and metal perchlorates7
akchakraborti@niper.ac.in
ReceiVed March 9, 2006
Magnesium bistrifluoromethanesulfonimide catalyzed the
acetylation of phenols, alcohols, and thiols under solvent-
free conditions at room temperature and in short times.
Electron-deficient and sterically hindered phenols provided
excellent yields. The catalyst was found to be general for
acylation with other anhydrides, such as propionic, isobutyric,
pivalic, chloroacetic, and benzoic anhydrides. The rate of
acylation was influenced by the electronic and steric factors
associated with the anhydride. The reaction with less
electrophilic anhydrides (e.g., chloroacetic and benzoic
anhydrides) required higher temperature (∼80 °C). Chemose-
lective acetylation, pivalation, and benzoylation took place
with acid-sensitive alcohols without any competitive dehy-
dration/rearrangement.
(2) (a) Nafion-H: Kumareswaran, R.; Pachamuthu, K.; Vankar, Y. D.
Synlett 2000, 1651-1654. (b) Yttria-zirconia: Kumar, P.; Pandey, R. K.;
Bodas, M. S.; Dongare, M. K. Synlett 2001, 206-209. (c) NBS: Karimi,
B.; Seradj, H. Synlett 2001, 519-520. (d) LiClO4: Nakae, Y.; Kusaki, I.;
Sato, T. Synlett 2001, 1581-1586. (e) Ionic liquid: Forsyth, S. A.;
MacFarlane, D. R.; Thompson, R. J.; Itzstein, M. V. Chem. Commun. 2002,
714-715. (f) Mg(ClO4)2: Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni,
E.; Massaccesi, M.; Rinaldi, S.; Sambri, L. Synlett 2003, 39-42. (g) Zn-
(ClO4)2: Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi,
M.; Sambri, L. Eur. J. Org. Chem. 2003, 4611-4617. (h) AlPW12O40:
Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F.; Amani, K. Chem. Commun
2003, 764-765. (i) RuCl3: De, S. K. Tetrahedron Lett. 2004, 45, 2919-
2922. (j) ZrOCl2: Ghosh, R.; Maiti, S.; Chakraborty, A. Tetrahedron Lett.
2004, 45, 147-151. (k) BiOCl: Ghosh, R.; Maiti, S.; Chakraborty, A.
Tetrahedron Lett. 2004, 45, 6775-6778. (l) Al2O3: Yadav, V. K.; Babu,
K. G. J. Org. Chem. 2004, 69, 577-580. (m) MoOCl2: Chen, C.-T.; Kuo,
J.-H.; Pawar, V. D.; Munot, Y. S.; Weng, S.-S.; Ku, C.-H.; Liu, C.-Y. J.
Org. Chem. 2005, 70, 1188-1197. (n) Mn(haacac)2Cl: Salavati-Niasari,
M.; Hydrazadeh, S.; Amiri, A.; Salavati, S. J. Mol. Catal. A 2005, 231,
191-195.
(3) (a) Cu(OTf)2: Chandra, K. L.; Saravanan, P.; Singh, R. K.; Singh,
V. K. Tetrahedron 2002, 58, 1369-1374. (b) In(OTf)3: Chauhan, K. K.;
Frost, C. G.; Love, I.; Waite, D. Synlett 1999, 1743-1744. (c) Bi(OTf)3:
Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. J. Org. Chem. 2001, 66,
8926-8934. (d) Ce(OTf)3: Dalpozzo, R.; De Nino, A.; Maiuolo, L.;
Procopio, A.; Nardi, M.; Bartoli, G.; Romeo, R. Tetrahedron Lett. 2003,
44, 5621-5624. (e) LiOTf: Karimi, B.; Maleki, J. J. Org. Chem. 2003,
68, 4951-4954. (f) Er(OTf)3: Procopio, A.; Dalpozzo, R.; De Nino, A.;
Maiuolo, L.; Russo, B.; Sindona, G. AdV. Synth. Catal. 2005, 346, 1465-
1470.
In the synthesis of multifunctional targets, one often needs
to carry out a reaction at a particular functional group in the
presence of other functional groups, such as phenol, alcohol,
and thiol, that are sensitive to the desired chemical transforma-
tion. Thus, the protection of phenols, alcohols, and thiols is one
of the most frequently employed reactions in organic synthesis
and is normally achieved by acylation with anhydrides in the
presence of suitable catalyst. Various organic (e.g., DMAP and
Bu3P) and inorganic (e.g., halides and triflates of transition and
rare earth metals) catalysts have been employed for this
purpose.1 The recent efforts for the development of newer
methods highlight the importance of heteroatom acylation.2,3
The reported methodologies suffer from one or more of the
following disadvantages: (i) potential health hazard [DMAP is
highly toxic (e.g., intravenous LD50 in the rat ) 56 mg/kg) and
Bu3P is flammable (flash point ) 37 °C), need to use
halogenated solvents]; (ii) difficulty in handling (Bu3P undergoes
aerial oxidation, and triflates are moisture sensitive); (iii) high
cost of the catalysts (e.g., triflates); (iv) requirement of special
(4) (a) HClO4-SiO2: Chakraborti, A. K.; Gulhane, R. Chem. Commun.
2003, 1896-1897. (b) BiOClO4: Chakraborti, A. K.; Gulhane, R.; Shivani.
Synlett 2003, 1805-1808. (c) Mg(ClO4)2: Chakraborti, A. K.; Sharma, L.;
Gulhane, R.; Shivani. Tetrahedron 2003, 59, 7661-7668. (d) HBF4-
SiO2: Chakraborti, A. K.; Gulhane, R. Tetrahedron Lett. 2003, 44, 3521-
3525. (e) Cu(BF4)2: Chakraborti, A. K.; Gulhane, R.; Shivani. Synthesis
2004, 111-115. (f) InCl3: Chakraborti, A. K.; Gulhane, R. Tetrahedron
Lett. 2003, 44, 6749-6753. (g) ZrCl4: Chakraborti, A. K.; Gulhane, R.
Synlett 2004, 627-630.
* To whom correspondence should be addressed. Fax: 91 (0)172 2214692.
Tel: 91 (0)172 2214683. E-mail: akchakraborti@niper.ac.in.
(1) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
(5) Olah, G. A.; Prakash, G. K. S. Superacids; Wiley: New York, 1985.
(6) Dumeunier, R.; Marko´, I. E. Tetrahedron Lett. 2004, 45, 825-882.
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999.
10.1021/jo0605142 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/20/2006
J. Org. Chem. 2006, 71, 5785-5788
5785

TABLE 1. Acylation of 1, 2, and 3 with Ac2O in the Presence of
Different Lithium and Magnesium Saltsa
becomes detrimental for their use for large-scale preparation.
Hence, we focused our attention to HNTf2 as it is a weaker
Brønsted acid than TfOH.8 It has been observed that the ligand
exchange does not take place with triflimides.9 Therefore, the
side reactions that are likely to occur as a result of in situ
liberation of HNTf2 will be avoided if a triflimide is used as a
catalyst. The 29Si chemical shift values in TMSNTf2 and
TMSOTf suggest that a metal triflimide should be a better Lewis
acid catalyst compared to the corresponding triflate.10 Thus,
metal triflimides may be considered as safe substitutes for metal
perchlorates.11 The use of Sc(NTf2)3 as a catalyst for acetylation
of alcohols and phenols has been reported.12 However, it is not
available commercially and involves a high cost for its prepara-
tion and therefore is not a good contender for general use.
Moreover, the strong acidic property of Sc(NTf2)3 necessitates
the use of solvent, a large excess of Ac2O, and low temperature
(-20 °C) for substrates that are likely to experience a side
reaction (e.g., tertiary alcohol). To choose a suitable metal salt
of HNTf2, we considered the alkali and alkaline earth metal
triflimides as the lower charge-size function of alkali and
alkaline earth metal cations compared to that of the Sc3+ ion
(Z2/r values of Li+, Mg2+, and Sc3+ ions are 1.35, 5.56, and
12.33 e2 m-10, respectively),13 which makes the alkali and
alkaline earth metal triflimides milder Lewis acids compared
to Sc(NTf2)3. The commercial availability and cheaper prices
of the alkali and alkaline earth metal triflimides make them
better suited for catalytic use. The higher hydrolysis constant
(pKh) values of 13.82 and 11.42 for Li+ and Mg2+, respectively,
compared to that of 4.6 for Sc3+ make the alkali metal triflimides
less susceptible to moisture (nonanhydrous conditions) compared
to Sc(NTf2)3.14 Thus, we used LiNTf2 and Mg(NTf2)2 during
the reaction of 2-naphthol (1), 4-nitrophenol (2), and 1-phen-
ylethanol (3) as representative unactivated phenol, electron-
deficient phenol, and secondary alcohol (acid-sensitive), re-
spectively, with Ac2O under neat conditions at room temperature
(Table 1). The corresponding acetates were formed in 92, 90,
and 95% yields, respectively, in the presence of Mg(NTf2)2
compared to the yields of 75, 80, and 28%, respectively,
obtained in the presence of LiNTf2, and we established that
Mg(NTf2)2 is the desired catalyst. To determine the crucial role
Yield (%)c
entry
catalyst (mol %)b
time (min)
1
2
3
1
2
3
4
5
LiNTf2 (5)
Mg(NTf2)2 (1)
MgCl2 (5)
MgBr2 (5)
MgI2 (5)
60
30
60
60
60
75
92
13
70
86
80
90
29
33
72
28
95d
nil
33
82
a The substrate (2.5 mmol) was treated with Ac2O (1.2 equiv) in the
presence of the catalyst under neat conditions at room temperature. b Molar
equiv of the catalyst used with respect to the substrate. c Isolated yield of
the corresponding acetate. d The reaction was carried out for 15 min.
TABLE 2. Mg(NTf2)2-Catalyzed Acylation of Phenols and Thiolsa
of the counteranion in imparting catalytic property to Mg2+
,
various magnesium salts were employed as catalysts for
acetylation of 1, 2, and 3 (Table 1). Comparison of the results
of entry 2 with those of entries 3-5 revealed the importance of
the use of the magnesium salt of HNTf2. The use of solvents,
(7) (a) Schumacher, J. C. Perchlorates: Their Properties, Manufacture
and Uses; ACS Monograph Series; Reinhold: New York, 1960. (b) Long,
J. Chem. Health Saf. 2002, 9, 12-18.
(8) Foropoulos, J.; DesMarteau, D. D. Inorg. Chem. 1984, 23, 3720-3123.
(9) Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Chem. Commun. 2002,
1564-1565.
(10) (a) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219-8226. (b)
Vij, A.; Zheng, Y. Y.; Kirchmeier, R. L.; Shreeve, J. M. Inorg. Chem. 1994,
33, 3281-3288. (c) Olah, G. A.; Laali, K.; Farooq, O. Organometallics
1984, 3, 1337-1340.
(11) (a) Handy, S. T.; Grieco, P. A.; Mineur, C.; Ghosez, L. Synlett 1995,
565-567. (b) Ghosez, L.; Mineur, C.; Tamion, R. Tetrahedron Lett. 1995,
36, 8977-8980.
a The substrate (2.5 mmol) was treated with Ac2O (1.2 equiv per OH/
SH) in the presence of Mg(NTf2)2 (1 mol %) under solvent-free conditions
at room temperature (except for entry 10). b Isolated yield of the corre-
sponding acylated products. c The reaction was carried out at 80 °C.
d Isolated yield of the diacetate. e Isolated yield of the triacetate.
(12) Ishihara, K.; Kubota, M.; Yamamoto, H. Synlett 1996, 265-266.
(13) Huheey, J. E. Inorganic Chemistry: Principles of Structure and
ReactiVity, 3rd ed.; Harper & Row: Singapore, 1983.
(14) (a) Yatsimirksii, K. B.; Vasil’ev, V. P. Instability Constants of
Complex Compounds; Pergamon: Elmsford, NY, 1960. (b) Bjerrum, B.,
Schwarzenbach, G., Sillen, L. G., Eds. Stability Constants of Metal-Ion
Complexes, Part II: Inorganic Ligands; The Chemical Society: London,
1958.
such as MeNO2, MeCN, Et2O, and DCM, was found to be
detrimental to the catalytic efficiency of Mg(NTf2)2 as revealed
by the formation of 2-acetoxynaphthalene in 22, 22, 17, and
22% yields after 1 h during the reaction of 2-hydroxynaphtha-
lene with Ac2O (1.2 equiv) at room temperature.
5786 J. Org. Chem., Vol. 71, No. 15, 2006

TABLE 3. Mg(NTf2)2-Catalyzed Acylation of Alcoholsa
TABLE 5. Mg(NTf2)2-Catalyzed Benzoylation of Representative
Phenols and Alcohols with (PhCO)2Oa
a The substrate (2.5 mmol) was treated with (PhCO)2O (1.2 equiv per
OH group) in the presence of Mg(NTf2)2 (1 mol %) under solvent-free
conditions at 80 °C (except for entry 7). b Isolated yield of the corresponding
benzoylated product. c The benzoylated product was obtained in 88% yield
after 1 h by carrying out the reaction at room temperature. d Isolated yield
of the dibenzoylated product. e The benzoylated product was obtained in
78% yield after 2 h by carrying out the reaction at room temperature. f The
reaction was carried out at room temperature.
a The substrate (2.5 mmol) was treated with Ac2O (1.2 equiv) in the
presence of Mg(NTf2)2 (1 mol %) under solvent-free conditions at room
temperature. b Isolated yield of the corresponding acylated product.
factors associated with the substrates. The distinct difference
in the rate of acylation of 2- and 1-hydroxynaphthalenes (entries
1 and 2) was due to the steric inhibition offered by the peri-
hydrogen of 1-hydroxynaphthalene toward the approach of the
electrophile. Excellent results were obtained with phenols that
are less nucleophilic due to the presence of electron-withdrawing
substituents, such as Br, Cl, COMe, CO2Me, NO2, and CN
(entries 4-9). The requirement of heating the reaction mixture
during the acylation of 2-nitrophenol (entry 10) was due to the
steric hindrance of the NO2 group at the ortho position of the
phenolic OH group in addition to the electron-withdrawing effect
in making 2-nitrophenol electron deficient.
The potential of Mg(NTf2)2 as a catalyst for acylation of
various alcohols was investigated next, and excellent results
were obtained when the reactions were carried out at room
temperature with 1.2 equiv of Ac2O in the presence of 1 mol
% of Mg(NTf2)2 (Table 3). Secondary and tertiary alcohols did
not undergo any side reactions, such as dehydration or rear-
rangement (entries 3, 4, 7, 9-13). No rearrangement was
observed for allylic (entry 8) and propargylic (entry 12) alcohols.
These observations exemplified chemoselectivity. The mildness
of the catalyst was tested with optically active substrates that
were acetylated without any detrimental effect on the optical
purity (entries 9-11) as determined by comparison of the optical
rotation value of the products with that of authentic compounds.
To establish Mg(NTf2)2 as a general acylation catalyst, 1 was
treated with various anhydrides (Table 4). Good to excellent
TABLE 4. Mg(NTf2)2-Catalyzed Acylation of 1 with (RCO)2Oa
entry
R
equivb
time (h)
yield (%)b
1
2
3
4
5
6
Me
1
1
1
1.5
1
0.5
1
1
0.5
1
1
92
100d
75e
88
Et
iPr
tBu
Ph
92f
ClCH2
1
70f
a The substrate (2.5 mmol) was treated with the anhydride in the presence
of Mg(NTf2)2 (1 mol %) under solvent-free conditions at room temperature
(except for entries 4 and 5). b Molar equiv of the anhydride used with respect
to the substrate. c Isolated yield of the corresponding acylated product. d A
99% yield was obtained in carrying out the reaction at 80 °C for 30 min.
e An 86% yield was obtained in carrying out the reaction at 80 °C for 30
min. f The reaction was carried out at 80 °C.
To explore the generality and scope, structurally diverse
phenols and thiols were subjected to acylation with Ac2O (1.2
equiv) at room temperature and under neat conditions in the
presence of Mg(NTf2)2 (1 mol %) (Table 2). The catalyst was
compatible with various functional groups, such as OMe, Br,
Cl, COMe, CO2Me, CN, and NO2, that were likely to undergo
complex formation with the catalyst and impede the acetylation
(entries 3-10). Di- and trihydroxy aromatic compounds afforded
the di- and triacetates, respectively, in excellent yields (entries
10-14). The reaction was influenced by the steric and electronic
J. Org. Chem, Vol. 71, No. 15, 2006 5787

Ce(OTf)3 (1 mol %).4f Acylation of 5 afforded 86% yield after
1 h when the reaction was carried out with 1.2 equiv of Ac2O
in the presence of Mg(NTf2)2 (1 mol %). However, comparable
yield was obtained after 15 h when 5 was treated with 5 equiv
of Ac2O in the presence of LiOTf (20 mol %).4g The Mg(NTf2)2-
catalyzed benzoylation of 1 and 2,4,6-trimethylphenol with
(PhCO)2O (1.2 equiv) afforded 88 and 76% yields after 1 and
2 h, respectively, at room temperature under solvent-free
conditions. Compared to these observations, 21% yield was
obtained by the treatment of phenol with (PhCO)2O (1.5 equiv)
in MeCN for 0.5 h in the presence of Sc(NTf2)3.14 Benzoylation
of menthol (6) with (PhCO)2O (1.5 equiv) in MeCN afforded
69% yield after 6 h in the presence of Sc(NTf2)314 compared to
78% yield obtained after 2 h at room temperature under solvent-
free conditions by the treatment of 6 with (PhCO)2O (1.2 equiv)
in the presence of Mg(NTf2)2.
TABLE 6. Mg(NTf2)2-Catalyzed Pivalation of Representative
Phenols and Alcohols with (tBuCO)2Oa
In conclusion, we have found that Mg(NTf2)2 is a new and
excellent catalyst for acylation of phenols, alcohols, and thiols
at room temperature and under solvent-free conditions. The
catalyst was general for acylation with a variety of anhydrides
and was effective in benzoylation and pivalation of phenols and
alcohols. The several unique properties of Mg(NTf2)2, such as
stability, commercial availability, ease of preparation, minimal
hygroscopic nature, and high Lewis acidity, make Mg(NTf2)2
useful for catalytic applications.15
a The substrate (2.5 mmol) was treated with (tBuCO)2O (1.5 equiv) in
the presence of Mg(NTf2)2 (1 mol %) under solvent-free conditions at 80
°C (except for entry 1). b Isolated yield of the corresponding benzoylated
product. c The reaction was carried out at room temperature.
yields were obtained at room temperature by reaction with
propionic, isobutyric, and pivalic anhydrides. However, acylation
with benzoic and chloroacetic anhydrides required heating at
80 °C as the phenyl group and the chlorine atom reduced the
electrophilic character of the carbonyl carbon of benzoic and
chloroacetic anhydrides, respectively.
As the combined effect of the electronic and steric factors of
the phenyl group makes benzoic anhydride less susceptible to
nucleophilic attack, benzoylation with benzoic anhydride is
difficult to carry out. Thus, we felt it necessary to evaluate the
catalytic effect of Mg(NTf2)2 for benzoylation of a few
representative phenols and alcohols with benzoic anhydride
(Table 5).
The excellent results obtained for the benzoylation reaction
prompted us to carry out the pivalation of a few representative
phenols and alcohols with pivalic anhydride (Table 6).
The following representative examples demonstrated the
mildness/superiority of Mg(NTf2)2 compared to metal triflates.
The Bi(OTf)3 (3 mol %)-catalyzed pivalation of 3-phenyl-2-
methyl-2-propanol (4) with (tBuCO)2O (3 equiv) in DCM (3
mL/mmol) at room temperature failed to afford the desired
product after 5 h,4e but 77% yield was obtained by the treatment
of 4 with (tBuCO)2O (1.5 equiv) after 30 min in the presence
of Mg(NTf2)2 (1 mol %) under solvent-free conditions. No
acylated product was obtained after 48 h by the treatment of
cinnamyl alcohol (5) with Ac2O (1.5 equiv) in the presence of
Experimental Section
Typical Procedure for Acylation. A mixture of 1 (360 mg, 2.5
mmol), Ac2O (0.24 mL, 3 mmol, 1.2 equiv), and Mg(NTf2)2 (14.6
mg, 0.025 mmol, 1 mol %) was stirred magnetically under neat
conditions at room temperature for 15 min. The reaction mixture
was diluted with H2O (10 mL) and extracted with Et2O (3 × 15
mL). The combined ethereal extracts were washed successively with
2% aqueous NaOH (15 mL) and saturated brine (15 mL), dried
(Na2SO4), and concentrated under reduced pressure to afford the
product, which was in full agreement (mp, IR, NMR, MS) with an
authentic sample of 2-acetoxynaphthalene. All the remaining reac-
tions were carried out following this standard procedure, except
that the reaction mixture was heated at 80 °C wherever applicable.
On each occasion, the product obtained after the routine workup
was of sufficient purity (spectral data) and did not require further
purification.
Acknowledgment. Shivani thanks CSIR, Delhi, Government
of India for the award of Senior Research Fellowship.
Supporting Information Available: Typical experimental
procedure, spectral data of all compounds, and scanned spectra of
unknown compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0605142
(15) Sibi, M. P.; Petrovic, G. Tetrahedron: Asymmetry 2003, 14, 2879-
2882 and references therein.
5788 J. Org. Chem., Vol. 71, No. 15, 2006